Basic fetoprotein (referrred to hereinafter as "BFP"), which is a known basic protein, has been found by one of the inventors of this application in serum, intestine and brain tissues of human fetus. It has been particularly called basic fetoprotein since it is basic in contrast to the known acidic fetoprotein. Furthermore, one of the inventors has established a radioimmunoassay system of said protein and found that the assay of said protein in serum would help to diagnose cancer and judge its condition and therapeutical effect thereon. In particular, it has been found that said fetoprotein is useful to examine the presence of cancer, differing from alpha-fetoprotein (referred to hereinafter as "AFP") which is useful to diagnose cancer of a particular organ.
The following references (1) to (7) may be cited for the above prior findings.
(1) Ishii, M. et al.: Studies on Feto-Neoplastic Antigen. Proceedings of The Japanese Cancer Association, The 34th Annual Meeting, p.173 (1975).
(2) Ishii, M.: Studies on novel basic fetoprotein found in various malignant tumors. Igaku no Ayumi (The Stride of Medicine), 100(3), 344-346 (1977).
(3) Ishii, M.: Basic fetoprotein. Igaku no Ayumi (The Stride of Medicine), 106(5), 273-281 (1978).
(4) Ishii, M.: A new carcinoembryonic protein characterized by basic property. Scand. J. Immunol., 8(Suppl.8), 611-620 (1978).
(5) Ishii, M.: Characterization of basic fetoprotein and clinical usefulness of BFP for immunodiagnosis of human cancer. Carcino-Embryonic Proteins. Chemistry, Biology, Clinical Applications, Vol. 1, Lehmann, F.-G. (ed.), Elsevier/North-Holland Biomedical Press, Amsterdam, 333-340 (1979).
(6) Ishii, M., Nishimura, K., Hattori, M., Kanda, Y. and Ishihara, A.: Postoperative surveillance in patients with stomach cancer and monitoring of immuno-and polychemotherapy in patients with leukemia by basic fetoprotein. Carcino-Embryonic Proteins. Chemistry, Biology, Clinical Applications, Vol. 2, Lehmann, F.-G. (ed.), Elsevier/North-Holland Biomedical Press, Amsterdam, 603-606 (1979).
(7) Ishii, M.: Clinical usefulness of basic fetoprotein for immunodiagnosis of human cancer. Compendium of Assay for Immunodiagnosis of Human Cancer. Development in Cancer Research, Herberman, R. B. (ed.), Vol. 1, Elsevier/North-Holland Biomedical Press, New York, 45-50 (1979).
(8) PROCEEDINGS, Sixth Annual Meeting of the Tumor Marker, Program Abstract, p.111, Oct. 20 (1986), Sapporo.
(9) PROCEEDINGS, Sixth Annual Meeting of the Tumor Marker, p.248-250, Oct. 20 (1986). Sapporo.
Since basic fetoprotein is present in the serum of cancer patients in a trace amount, it is necessary to establish a highly sensitive assay system to determine it. RIA and EIA methods have been mainly developed therefor. Detailed descriptions of the RIA method are found in the references (3) to (7) as cited above. Detailed descriptions of the EIA method are found in the following references (10) and (11).
(10) Ishii, M. et al.: Basic fetoprotein, present clinical function test--enforcement and interpretation thereof. Nippon Rinsho 37, 1536-1539 (1979).
(11) Ishii, M.: Basic fetoprotein: Rinsho Kensa 24, (8), 931-936 (1980).
Subsequently, the inventors have succeeded in obtaining monoclonal anti-basic fetoprotein antibodies. Preparation and evaluation of said monoclonal antibodies are described in the following reference (12).
(12) Ishii, M. et al.: Production of Monoclonal Anti-Basic Fetoprotein (BFP) and Usefulness of Monoclonal Anti-BFP for Immuno-diagnosis of Human Cancer, Tumor Research, Vol. 18, (Special Issue),1983 p75-86.
The reaction specificities for basic fetoprotein of the monoconal antibodies thus obtained were examined by the EIA and MO (Micro-Ouchterlony) methods. Consequently, it was found that there are at least three different antigenic determinants on the basic fetoprotein molecule and that the monoclonal antibodies might be classified into three types corresponding to each antigenic determinant. Examples of monoclonal antibodies corresponding to the three antigenic determinants A, B and C are as follows:
______________________________________ antigenic determinant monoclonal antibody ______________________________________ A 5C4, 5C5, 5C6, 7D1, K1 B 5B3, 5C2 C 5A2, 5A3, 7D3, 8A2, 7B4, 5D6-2, 8A1, 7A5, 8A5, 7B6 ______________________________________
Based on the above findings, the inventors have established a highly sensitive method for assaying basic fetoprotein in serum by a sandwich method with the use of these monoclonal antibodies (Japanese Patent Application Laying Open (KOKAI) No. 80768/1985).
However, all the assay methods referred to in the above are directed to BFP in serum. On the other hand, no evidence has been obtained up to now that BFP may be detected in urine of healthy donors or patients with various diseases.
When assayed using urine, no significant difference was obtained with respect to an amount of well known tumor markers such as carcinoembryonic antigen (CEA), AFP and the like between healthy donors and patients with cancer. Particularly a tumor marker which is useful in diagnosing urogenital cancer has not yet been found.
The present inventors have found the presence of BFP in urine of healthy donors and patients with various diseases as well, and have studied its utility as a tumor marker, leading to the perfection of the present invention.